Pharmaceutical composition containing optically active compound having thrombopoietin receptor agonist activity, and intermediate therefor

ABSTRACT

An optically active 4-phenylthiazole derivative having a thrombopoietin receptor agonist activity and a pharmaceutical composition containing the present compound as an active ingredient are created, and a platelet production regulating agent which can be orally administered is provided. 
     Disclosed is a pharmaceutical composition containing, as an active ingredient, an optically active compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein, R 1  is a halogen atom or C1-C3 alkyloxy; R 2  is C1-C8 alkyl; R 3  is C1-C8 alkyl; R 4  and R 5  are each independently a fluorine atom or chlorine atom; R 6  is C1-C3 alkyl or C1-C3 alkyloxy; * indicates that a carbon atom marked with an asterisk is an asymmetric carbon,
 
a pharmaceutically acceptable salt thereof, or a solvate thereof.

TECHNICAL FIELD

The present invention relates to a pharmaceutical compositioncontaining, as an active ingredient, an optically active4-phenylthiazole derivative having a thrombopoietin receptor agonistactivity.

BACKGROUND ART

Since thrombopoietin is a polypeptide cytokine consisting of 332 aminoacids and it promotes platelet production by stimulating differentiationand proliferation of a megakaryocyte via a receptor, it is expected asan agent for morbidity of a blood disease accompanied with abnormalityof the platelet number such as thrombocytopenia. A nucleotide sequenceof a gene encoding a thrombopoietin receptor is described in Non-PatentDocument 1. In Patent Document 1 and Patent Document 2, low-molecularpeptides having affinity for the thrombopoietin receptor are also known,but oral administration of these peptide derivatives are not generallypractical.

As a low-molecular compound having affinity for the thrombopoietinreceptor, a 1,4-benzothiazepine derivative is described in PatentDocument 3 and Patent Document 4, a 1-azonaphthalene derivative isdescribed in Patent Document 5, and a 1,3-thiazole derivative isdescribed in Patent Document 6 to 22.

[Patent Document 1]

Japanese Patent Application Laid-Open (JP-A) No. 10-72492

[Patent Document 2]

International Publication WO 96/40750

[Patent Document 3]

JP-A No. 11-1477

[Patent Document 4]

JP-A No. 11-152276

[Patent Document 5]

International Publication WO 00/35446

[Patent Document 6]

JP-A No. 10-287634

[Patent Document 7]

International Publication WO 01/07423

[Patent Document 8]

International Publication WO 01/53267

[Patent Document 9]

International Publication WO 02/059099

[Patent Document 10]

International Publication WO 02/059100

[Patent Document 11]

International Publication WO 02/059100

[Patent Document 12]

International Publication WO 02/062775

[Patent Document 13]

International Publication WO 2003/062233

[Patent Document 14]

International Publication WO 2004/029049

[Patent Document 15]

International Publication WO 2005/007651

[Patent Document 16]

International Publication WO 2005/014561

[Patent Document 17]

JP-A No. 2005-47905

[Patent Document 18]

JP-A No. 2006-219480

[Patent Document 19]

JP-A No. 2006-219481

[Patent Document 20]

International Publication WO 2007/004038

[Patent Document 21]

International Publication WO 2007/036709

[Patent Document 22]

International Publication WO 2007/054783

[Non-Patent Document 1]

Proc. Natl. Acad. Sci. USA, 1992, vol. 89, p. 5640-5644

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

A pharmaceutical composition containing, as an active ingredient, anoptically active 4-phenylthiazole derivative having a thrombopoietinreceptor agonist activity is created, and a platelet productionregulating agent which can be orally administered is provided.

Means to Solve the Problems

In view of the above points, the present inventors have continued tostudy intensively and, as a result, found out a pharmaceuticalcomposition containing, as an active ingredient, the following opticallyactive 4-phenylthiazole derivative, exhibiting the excellentthrombopoietin receptor agonist activity, and exhibiting the high oralabsorbability and/or high in vivo activity, a crystal having highstability and/or high purity, as well as a useful intermediate and acrystal thereof.

That is, the present invention relates to 1) a pharmaceuticalcomposition containing, as an active ingredient, an optically activecompound represented by the formula (I):

wherein R¹ represents a halogen atom or C1-C3 alkyloxy; R² representsC1-C8 alkyl; R³ represents C1-C8 alkyl; R⁴ and R⁵ each representindependently a fluorine atom or a chlorine atom; R⁶ represents C1-C3alkyl or C1-C3 alkyloxy; * indicates that a carbon atom marked with anasterisk is an asymmetric carbon, a pharmaceutically acceptable saltthereof, or a solvate thereof.

The present invention further relates to the following 2) to 23).

2) The pharmaceutical composition according to 1), wherein R¹ ismethyloxy.3) The pharmaceutical composition according to 1) or 2), wherein R⁴ andR⁵ are both a chlorine atom.4) The pharmaceutical composition according to any one of 1) to 3),wherein R⁶ is methyl.5) The pharmaceutical composition according to 1), wherein R¹ ismethyloxy, R⁴ and R⁵ are both a chlorine atom, and R⁶ is a methyl.6) The pharmaceutical composition according to any one of 1) to 5),which is a thrombopoietin receptor agonist.7) The pharmaceutical composition according to any one of 1) to 5),which is a platelet production regulating agent.8) Use of an optically active compound represented by the formula (I):

wherein R¹ represents a halogen atom or C1-C3 alkyloxy; R² representsC1-C8 alkyl; R³ represents C1-C8 alkyl; R⁴ and R⁵ each representindependently a fluorine atom or a chlorine atom; R⁶ represents C1-C3alkyl or C1-C3 alkyloxy; * indicates that a carbon atom marked with anasterisk is an asymmetric carbon, a pharmaceutically acceptable saltthereof, a solvate thereof for manufacturing a medicament for regulatinga platelet production.9) A method of regulating a platelet production of a mammal, comprisingadministering an amount exhibiting a therapeutic effect of an opticallyactive compound represented by the formula (I):

wherein R¹ represents a halogen atom or C1-C3 alkyloxy; R² representsC1-C8 alkyl; R³ represents C1-C8 alkyl; R⁴ and R⁵ each representindependently a fluorine atom or a chlorine atom; R⁶ represents C1-C3alkyl or C1-C3 alkyloxy; * indicates that a carbon atom marked with anasterisk is an asymmetric carbon, a pharmaceutically acceptable saltthereof, or a solvate thereof to a mammal including a human.10) A crystal of(S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid having a diffraction angle 2θ of a main peak of powder X-raydiffraction of 4.2, 6.4, 12.3, 13.2, 23.6, 23.8, and 24.7 degrees.11) A crystal of(S)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid having a diffraction angle 2θ of a main peak of powder X-raydiffraction of 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees.12) A crystal of(S)-(E)-3-(2,6-dichloro-4-{4-[3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid having a diffraction angle 2θ of a main peak of powder X-raydiffraction of 13.6, 16.1, 21.2, 23.4 and 24.5 degrees.13) A pharmaceutical composition containing, as an active ingredient,the crystal of the optically active compound as defined in any one of10) to 12), the crystal of a pharmaceutically acceptable salt thereof,or the crystal of a solvate thereof.14) The pharmaceutical composition according to 13), which is athrombopoietin receptor agonist.15) The pharmaceutical composition according to 14), which is a plateletproduction regulating agent.16) Use of the crystal as defined in any one of 10) to 12) formanufacturing a medicament for regulating a platelet production.17) A method of regulating a platelet production of a mammal, comprisingadministering an amount exhibiting a therapeutic effect of the crystalas defined in any one of 10) to 12) to a mammal including a human.18) A crystal of(S)-4-[2-methyloxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-yl amine havinga diffraction angle 2θ of a main peak of powder X-ray diffraction of10.3, 17.7, 18.2, 18.5 and 23.1 degrees.19) A crystal of(S)-(−)-4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-yl aminehaving a diffraction angle 2θ of a main peak of powder X-ray diffractionof 12.5, 13.0, 13.6, 16.4, 23.0 and 24.3 degrees.20) A crystal of ethyl 3-(4-carboxy-2,6-dichlorophenyl)-2-methylmethacrylate having a diffraction angle 2θ of a main peak of powderX-ray diffraction of 8.1, 16.3, 19.2, 20.0, 24.8 and 39.0 degrees.21) An optically active compound represented by the formula (I), apharmaceutically acceptable salt thereof, or a solvate thereof as aplatelet production regulating agent.22) An optically active compound represented by the formula (I), apharmaceutically acceptable salt thereof, or a solvate for regulating aplatelet production.23) The optically active compound according to 21) or 22), apharmaceutically acceptable salt thereof, or a solvate thereof, whereinR¹ is methyloxy.24) The optically active compound according to 21) or 22), apharmaceutically acceptable salt thereof, or a solvate thereof, whereinR⁴ and R⁵ are both a chlorine atom.25) The optically active compound according to any one of 1) to 3), apharmaceutically acceptable salt thereof, or a solvate thereof, whereinR⁶ is methyl.26) The optically active compound according to 21), a pharmaceuticallyacceptable salt thereof, or a solvate thereof, wherein R¹ is methyloxy,R⁴ and R⁵ are both a chlorine atom, and R⁶ is methyl.

The meaning of each term will be explained below. Each term is used asunified meaning herein, and is used in the same meaning when used aloneor when used in combination with other terms.

Herein, the “halogen atom” means a fluorine atom, a chlorine atom, abromine atom, or an iodine atom. A fluorine atom, a chlorine atom, and abromine atom are preferable.

Herein, the “alkyl” includes a straight or branched monovalenthydrocarbon group of a carbon number of 1 to 8. Examples include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl orthe like. Preferably, C1-C6 alkyl is exemplified Further, C1-C4 alkyl ispreferred. Particularly, when a carbon number is designated, “alkyl”having a carbon number in the number range is meant.

Herein, examples of “alkyloxy” include methyloxy, ethyloxy, n-propyloxy,isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy,n-pentyloxy, isopentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy,isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy or thelike. Preferably, C1-C6 alkyloxy is exemplified. Further, C1-C4 alkyloxyis preferred. Particularly, a carbon number is designated, “alkyloxy”having a carbon number in the number range is meant.

Herein, in the chemical formulas, a carbon atom marked with * means anasymmetric carbon. A compound marked with * means an optical isomerwhich absolute configuration of a carbon atom marked with * is Rconfiguration or S configuration. For example, an optically activecompound represented by the formula (I) includes an optical isomer of Rconfiguration ((R)-I)) or an optical isomer of R configuration ((S)-I)).

Herein, the “platelet production regulating agent” includes an agent formorbidity of a blood disease accompanied with abnormality of theplatelet number such as thrombocytopenia (thrombocytopenia afterhematopoietic stem cell transplantation (such as bone marrowtransplantation) and the like, thrombocytopenia after chemical therapy,hypoplastic anemia, myelodysplastic syndrome, acquired thrombocytopeniasuch as idiopathic thrombocytopenic purpura and the like, congenitalthrombocytopenia such as thrombopoietin deficiency and the like, viruspneumonia (such as hepatitis C and the like), other hepatic disease(hepatocirrhosis)) and the like. For example, the agent can be used fortreating and/or preventing an abnormality of the platelet number due toadministration of an anti-cancer agent for hematopoietic organ tumor,solid tumor or the like. When the platelet number is reduced byadministration of an anti-cancer agent, the agent can be used as atreating agent and, when reduction in the platelet number due toadministration of an anti-cancer agent is expected, the agent can beused as a preventive. When platelet reduction is expected atcardiovascular (such as heart blood vessel) surgical operation, theagent can be used as a therapeutic agent and/or a preventive.

Herein, the “platelet production is regulated” includes 1) increase inthe decreased platelet number, 2) maintenance of the platelet numberwhich will be decreased, and 3) reduction in a decreasing degree of theplatelet number.

A preferable substituent group of R¹ to R⁶ of the compound representedby the formula (I) is represented by (Ia) to (In). A compound of apossible combination thereof is preferable.

R¹ is (Ia) preferably a halogen atom or C1-C3 alkyloxy, (Ib) morepreferably a fluorine atom or methyloxy, and (Ic) most preferablymethyloxy.

R² is (Id) preferably C1-C8 alkyl, and (Ie) more preferably C1-C6 alkyl.

R³ is (If) preferably C1-C8 alkyl, and (Ig) more preferably C1-C6 alkyl.

R⁴ and R⁵ are both the same, and are (Ih) preferably a fluorine atom ora chlorine atom, and (Ii) more preferably a chlorine atom.

R⁶ is (Ij) preferably C1-C3 alkyl or C1-C3 alkyloxy, (Ik) morepreferably C1-C3 alkyl, and (II) most preferably methyl.

Optical rotation of an optical isomer is (Im) preferably (+) or (−), and(In) more preferably (−).

In addition, as the optically active compound represented by the formula(I), the following optically active compound is preferable.

wherein Me represents methyl; * indicates that a carbon atom marked withan asterisk is an asymmetric carbon.

EFFECT OF THE INVENTION

Since an optically active 4-phenylthiazole derivative having a strongthrombopoietin receptor antagonist activity exhibits a high oralabsorbability or/and a high in vivo activity, and has a high safety, apharmaceutical composition containing the optically active4-phenylthiazole derivative as an active ingredient is useful as,particularly, a platelet production regulating agent. In addition, acrystal has a high stability and/or a high purity, and an intermediatehas a high stability, and they are useful in producing a4-phenylthiazole derivative and/or producing a pharmaceuticalcomposition.

The optically active compound of the formula (I) can be synthesized bythe following production methods A to F and the like.

Production Method A

wherein R¹, R², R³, R⁴, R⁵, and R⁶ are as defined in 1); R⁷ and R⁸ areeach independently a chlorine atom, a bromine atom, or an iodine atom;R⁹ is a fluorine atom, a chlorine atom, or a bromine atom; R¹⁰ is C1-C6alkyl.

As a compound represented by the formula (II) as a starting compound, acommercially available product can be used.

A production method A is a method of producing an optically activecompound represented by the formula (I) from a compound represented bythe formula (II) via the first step to the sixth step.

The first step is a step of treating the compound represented by theformula (II) with magnesium in a solvent to produce a Grignard reagent,and reacting the reagent with a compound represented by the formula: R²CHO (wherein R² is as defined in 1)) to produce a compound representedby the formula (IV).

Relative to the compound represented by the formula (II), magnesium canbe used at 0.5 to 2 mol equivalents, and the compound represented by theformula: R² CHO can be used at 0.5 to 3 mol equivalents.

As the solvent, tetrahydrofuran or the like can be used.

A reaction temperature can be 0° C. to a reflux temperature of asolvent, and a reaction time can be 0.5 to 12 hours.

The second step is a step of alkylating the compound represented by theformula (IV) by using an alkylating agent in the presence of a base toproduce a compound represented by the formula (V).

Relative to the compound represented by the formula (IV), the alkylatingagent can be used at 0.5 to 2 mol equivalents and, the base can be usedat 0.5 to 5 mol equivalents.

As the solvent, N,N-dimethylformamide, tetrahydrofuran and the like canbe used alone, or by mixing them.

As the base, sodium hydride, sodium hydroxide, potassium hydroxide,potassium carbonate, cesium carbonate and the like can be used alone, orby mixing them. A reaction temperature can be −10° C. to a refluxtemperature of a solvent, and a reaction time can be 0.5 to 12 hours.

The third step is a step of treating the compound represented by theformula (V) with isopropyl magnesium chloride in a solvent to produce aGrignard reagent, and reacting the reagent with a compound representedby the formula: X—C(═O)—CH₂—R⁹ (wherein R⁹ is as defined above; X is ahalogen atom) to produce a compound represented by the formula (VI).

Relative to the compound represented by the formula (V), isopropylmagnesium chloride can be used at 0.5 to 2 mol equivalents, and thecompound represented by the formula: R⁹—CH₂—C(═O)—X (wherein R⁹ and Xare as defined above) or the formula: R⁹—CH₂—C(═O)—N(Me)(OMe) (wherein Ris as defined above; Me is methyl) can be used at 0.5 to 3 molequivalents.

As the solvent, tetrahydrofuran or the like can be used.

A reaction temperature can be 0° C. to a reflux temperature of asolvent, and a reaction time can be 0.5 to 12 hours.

The fourth step is a step of reacting the compound represented by theformula (VI) with thiourea in a solvent to produce a compoundrepresented by the formula (VII).

Relative to the compound represented by the formula (VI), thiourea canbe used at 0.5 to 2 mol equivalents.

As the solvent, methanol, ethanol, propanol, isopropanol and the likecan be used alone, or by mixing them.

A reaction temperature can be 20° C. to a reflux temperature of asolvent, and a reaction time can be 0.5 to 48 hours.

The fifth step is a step of reacting the compound represented by theformula (VII) with a compound represented by the formula (IX) obtainedin a production method B to produce a compound represented by theformula (X).

The present step can be conducted by using the same method as the methoddescribed in the fourth step of an A method of International PublicationWO 2005/014561.

The sixth step is a step of producing a compound represented by theformula (I) by hydrolyzing the compound represented by the formula (X)in a solvent.

The present step can be conducted by using the same method as the methoddescribed in the fifth step of an A method of International PublicationWO 2005/014561.

The compound obtained in each step can be isolated and purified by ageneral method such as silica gel column chromatography,recrystallization, and/or distillation. Alternatively, the resultingcompound can be also used in a next reaction without purification. Whenthe compound obtained in each step is a racemic compound, an opticallyactive compound is obtained by column chromatography using a chiralcolumn, and each step may be also performed using it.

Production Method B

wherein R⁴, R⁵ and R⁶ are as defined in 1); R¹⁰ is as defined in aproduction method A. As a compound represented by the formula (VIII) asa starting compound, a commercially available product can be used.

A production method B is a method of producing a compound represented bythe formula (IX) from the compound represented by the formula (VIII).The compound represented by the formula (IX) is subjected to the fifthstep of a production method A, and is further subjected to the sixthstep, thereby, the compound represented by the formula (I) can beproduced.

The present step can be conducted by using the same method as the methoddescribed in the second step of an A method of International PublicationWO 2005/014561.

The compound obtained in each step can be isolated and purified by ageneral method such as silica gel column chromatography,recrystallization, and/or distillation. Alternatively, the resultingcompound can be also used in a next reaction without purification.

Production Method C

wherein R¹, R², R³, R⁴, R⁵, and R⁶ are as defined in 1); R¹⁰ is asdefined in a production method A.

As the compound represented by the formula (VII) as a starting compound,the compound produced by a production method A can be used.

A production method C is a method of producing the compound representedby the formula (X) from the compound represented by the formula (VII)via the first step and the second step. The compound represented by theformula (X) can be subjected to the sixth step of a production method Ato obtain the compound represented by the formula (I).

In the first step, using the same method as the fifth step of aproduction method A, the compound represented by the formula (XI) can beobtained by reacting the compound represented by the formula (VII) andthe compound represented by the formula (VIII).

In the second step, using the same method as a production method B, thecompound represented by the formula (X) can be obtained from a compoundrepresented by the formula (XI).

The compound obtained in each step can be isolated and purified by ageneral method such as silica gel column chromatography,recrystallization, and/or distillation. Alternatively, the resultingcompound can be also used in a next reaction without purification. Whenthe compound obtained in each step is a racemic compound, an opticallyactive compound is obtained by column chromatography using a chiralcolumn, and each step may be also performed using it.

Production Method D

wherein R¹ and R² are as defined in 1); R⁷ and R⁸ are as defined in aproduction method A.

As the compound represented by the formula (II) as a starting compound,a commercially available product can be used.

A production method D is a method of producing the optically activecompound represented by the formula (IV) from the compound representedby the formula (II) via the first step and the second step. Bysubjecting the optically active compound represented by the formula (IV)to the second step to the sixth step of the production method A, theoptically active compound represented by the formula (I) can beobtained.

The first step is a step of producing the compound represented by theformula (IV) by treating the compound represented by the formula (II)with magnesium in a solvent to produce a Grignard reagent, and reactingthis with a compound represented by the formula: R²—C(═O)—X (wherein R²is as defined in 1); X is as defined as above) or the formula:R²—C(═O)—N(Me)(OMe) (R² is as defined in 1); Me is methyl).

Relative to the compound represented by the formula (II), magnesium canbe used at 0.5 to 2 mol equivalents, and the compound represented by theformula: R²—C(═O)—X wherein R² is as defined in 1); X is as defined asabove or the formula: R²—C(═O)—N(Me)(OMe) wherein R² is as defined in1); Me is methyl can be used at 0.5 to 3 mol equivalents.

As the solvent, tetrahydrofuran or the like can be used.

A reaction temperature can be 0° C. to a reflux temperature of asolvent, and a reaction time can be 0.5 to 12 hours.

The second step is a step of asymmetric-reducing the compoundrepresented by the formula (III) with an asymmetric reductive reagent ina solvent to produce the compound represented by the formula (IV). Bysubjecting the compound represented by the formula (IV) to the thirdstep to the sixth step of the production method A, the compoundrepresented by the formula (I) can be obtained.

Relative to the compound represented by the formula (III), theasymmetric reducing reagent can be used at 0.5 to 2 mol equivalents.

As the solvent, toluene, tetrahydrofuran and the like can be used alone,or by mixing them.

As the asymmetric reductive reagent, R-CBS or the like can be used.

R-CBS is an optically active compound represented by the formula:

wherein Me is methyl; Ph is phenyl.

A reaction temperature can be −20° C. to a reflux temperature of asolvent, and a reaction time can be 0.5 to 12 hours.

The compound obtained in each step can be isolated and purified by ageneral method such as silica gel column chromatography,recrystallization, and/or distillation. Alternatively, the resultingcompound can be also used in a next reaction without purification.

Production Method E

wherein R⁴ and R⁵ are as defined in 1); R¹⁰ is as defined in aproduction method A; R¹¹ is a bromine atom or a iodine atom.

As a compound represented by the formula (XII) as a starting compound, acommercially available product can be used.

A production method E is a method of producing a compound represented bythe formula (XIV) from the compound represented by the formula (XII) viaa first step and a second step.

The first step is a step of producing a compound represented by theformula (XIII) by diazotizing the compound represented by the formula(XII) with sodium nitrite in a solvent in the presence of an acid,reacting this with alkyl acrylate, and ozonolysis the resultingcompound.

Relative to the compound represented by the formula (XII), sodiumnitride can be used at 0.5 to 3 mol equivalents, and alkyl acrylate canbe used at 0.5 to 3 mol equivalents.

As the solvent in diazotization, acetone or the like can be used. As thesolvent in ozonolysis, dichloromethane or the like can be used.

In diazotization and ozonolysis, each independently, a reactiontemperature can be −78° C. to a reflux temperature of a solvent, and areaction time can be 0.5 to 12 hours.

In the second step, using the same method as a production method B, thecompound represented by the formula (XIV) can be obtained from thecompound represented by the formula (XIII).

The compound obtained in each step can be isolated and purified by ageneral method such as silica gel column chromatography,recrystallization, and/or distillation. Alternatively, the resultingcompound can be also used in a next reaction without purification.

Production Method F

wherein R¹, R², R³, R⁴, R⁵, and R⁶ are as defined in 1); R¹⁰ is asdefined in a production method A; R¹¹ is a bromine atom or an iodineatom.

As the compound represented by the formula (VII) as a starting compound,the compound produced by a production method A can be used.

A production method F is a method of condensing the compound representedby the formula (VII) and the compound represented by the formula (XIV)to produce the compound represented by the formula (X). By subjectingthe compound represented by the formula (X) to the sixth step of aproduction method A, the compound represented by the formula (I) can beobtained.

The present step can be conducted by using the same method as the methoddescribed in the second step of C method of International Publication WO2005/014561.

The compound obtained in each step can be isolated and purified by ageneral method such as silica gel column chromatography,recrystallization, and/or distillation. Alternatively, the resultingcompound can be also used in a next reaction without purification.Alternatively, an optically active compound is obtained by columnchromatography using a chiral column, and each step may be performedusing it.

Regarding the crystal of the optically active compound represented bythe formula (I) produced by the aforementioned production methods, thecrystal of the optically active compound represented by the formula(VII), and the crystal of the compound represented by the formula (IX),a X-ray diffraction pattern can be obtained by powder X-ray diffraction.

Since the crystal is stable, is easily handled for performing the aboveproduction steps, or producing a pharmaceutical composition containing,as an active ingredient, the optically active compound represented bythe formula (I), and has a high purity, it is a useful crystal forproducing a pharmaceutical composition.

Regarding the crystal of the optically active compound represented bythe formula (I), the crystal of the optically active compoundrepresented by the formula (VII), and the crystal of the compoundrepresented by the formula (IX), a X-ray diffraction pattern is shown inExamples 3 to 5 described later (X-ray diffraction measurementcondition: vacuum tube CuK α-ray, tubular voltage 40 Kv, tubular current40 mA or 50 mA, d sin θ=nλ, (n is an integer, d is spacing (unit:Angstrom), θ is diffraction angle (unit: degree))).

These crystals are characterized by values of each diffraction angle orspacing.

Herein, examples of the “pharmaceutically acceptable salt” include saltswith alkali metals (such as lithium, sodium, and potassium), alkalineearth metals (such as magnesium and calcium), ammonium, organic basesand amino acid, or salts with inorganic acids (such as hydrochloricacid, hydrobromic acid, phosphoric acid, and sulfuric acid), and organicsalts (such as acetic acid, citric acid, maleic acid, fumaric acid,benzenesulfonic acid, and p-toluenesulfonic acid). These salts can beformed by normally performed methods.

Herein, the “solvate” includes, for example, a solvate with an organicsolvent, a hydrate and the like. When a solvate is formed, the compoundmay be coordinated with an arbitrarily number of solvent molecules.

The present pharmaceutical composition exhibits excellent thrombopoietinreceptor agonist activity as described in Test Examples descried later,and can be used as an agent (platelet production regulating agent) formorbidity of a blood disease accompanied with an abnormality of theplatelet number such as thrombocytopenia (thrombocytopenia afterhematopoietic stem cell transplantation (such as bone marrowtransplantation) and the like, thrombocytopenia after chemical therapy,hypoplastic anemia, myelodysplastic syndrome, acquired thrombocytopeniasuch as idiopathic thrombocytopenic purpura and the like, congenitalthrombocytopenia such as thrombopoietin deficiency and the like, viruspneumonia (such as hepatitis C and the like), other hepatic disease(hepatocirrhosis)) and the like. The composition can be used fortreating and/or preventing an abnormality of the platelet number due toadministration of an anti-cancer agent for hematopoietic organ tumor,solid tumor or the like. The composition can be used for treating and/orpreventing thrombocytopenia at surgical operation such as cardiovascularsystem (such as heart blood vessel) or the like.

When the present pharmaceutical composition is administered to a humanfor the purpose of treating the above diseases, it can be orallyadministered as powders, granules, tablets, capsules, pills, solutionsor the like, or can be parenterally administered as injectables,suppositories, transdermal absorbing agents, inhalation or the like. Inaddition, an effective amount of the present compound is mixed, ifnecessary, with pharmaceutical additives such as excipients, binders,wetting agents, disintegrating agents, lubricants or the like which aresuitable for its dosage form, thereby, a pharmaceutical preparation canbe obtained. In the case of injectables, the compound together with asuitable carrier is subjected to sterilization treatment intopreparations.

A dose is different depending on the stage of a disease, anadministration route, an age or a weight of a patient and, when orallyadministered to an adult, is usually 0.01 to 100 mg/kg/day, preferably0.02 to 10 mg/kg/day, most preferably 0.05 to 5 mg/kg/day.

The present invention will be explained in more detail below by way ofExamples and Test Examples, but the present invention is not limitedthereto.

In Examples, the following abbreviations are used.

R-CBS: Optically active compound represented by the formula:

wherein Me is methyl; Ph is phenyl.

Me: Methyl DMF: N,N-dimethylformamide THF: Tetrahydrofuran DMSO:Dimethylformamide

HPLC: High pressure liquid chromatography

EXAMPLES Reference Example 1 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{-4-[2-methyoxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (B-1)

First Step: Synthesis of (RS)-2-bromo-6-(1-hydroxyheptyl)anisole (1)

To a THF solution of 2,6-dibromoanisole (10 g, 37.6 mmol) was added Mg(0.90 g, 37.6 mmol), and the mixture was heated and stirred at 40° C.Under ice-cooling, n-heptanal (47.2 g, 41.3 mmol) was added dropwise.Aqueous hydrochloric acid solution was added to the reaction mixture,this was extracted with ethyl acetate, and the solvent was distilled offto obtain 8.95 g of a compound (1).

NMR (CDCl₃) δ ppm: 7.45-7.48 (m, 1H), 7.35-7.38 (m, 1H), 7.01 (t, 1H,8.1 Hz), 4.96-5.00 (m, 1H), 3.88 (s, 3H), 1.70-1.80 (m, 2H), 1.25-1.63(m, 8H), 0.85-0.90 (m, 3H)

Second Step: Synthesis of(RS)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (2)

(RS)-2-bromo-6-(1-hydroxyheptyl)anisole (1, 5.36 g, 17.8 mmol) obtainedin the first step and iodomethane (3.0 g, 21.3 mmol) were dissolved inTHF, and sodium hydride (0.78 g, 19.6 mmol) was added thereto underice-cooling. Under ice-cooling, hydrochloric acid was added, followed byextraction with ethyl acetate. After the solvent was distilled off, theresidue was purified by silica gel chromatography to obtain 4.92 g of acompound (2).

NMR (CDCl₃) δ ppm: 7.46 (d, 1H, J=8.1 Hz), 7.33 (d, 1H, J=4.5 Hz), 7.02(t, 1H, J=7.5 Hz), 4.52 (dd, 1H, J=7.5 Hz, J=4.8 Hz), 3.85 (s, 3H), 3.21(s, 3H), 1.27-1.80 (m, 10H), 0.84-0.90 (m, 3H)

Third Step: Synthesis of(RS)-2-chloro-1-[2-methyloxy-3-(1-methyloxypeptyl)phenyl]ethanone (3)

To a THF solution of(RS)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (2, 6.3 g, 20mmol) obtained in the second step was added dropwise 2Misopropylmagnesium chloride (20 mL).2-Chloro-N-methyloxy-N-methylacetamide (5.5 g) was added thereto, andthe mixture was stirred at room temperature. To the reaction solutionwas added aqueous hydrochloride acid solution, followed by extractionwith ethyl acetate. After the solvent was distilled off, the residue waspurified by silica gel chromatography to obtain 2.80 g of a compound(3).

NMR (CDCl₃) δ ppm: 7.58-7.61 (m, 1H), 7.51-7.54 (m, 1H), 7.22-7.27 (m,1H), 4.72 (dd, 2H, J=20.8 Hz, 15.9 Hz), 4.54 (dd, 1H, J=8.1 Hz, 4.8 Hz),3.78 (s, 3H), 3.22 (s, 3H), 1.14-1.77 (m, 10H), 0.84-0.90 (m, 3H)

Fourth Step: Synthesis of(RS)-4-[2-methyloxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylamine (A-1)

(RS)-2-chloro-1-[2-methyloxy-3-(1-methyloxypeptyl)phenyl)ethanone (3,0.28 g, 0.89 mmol) obtained in the third step and thiourea (0.10 g, 0.89mmol) were dissolved in ethanol, and the solution was heated andstirred. To the reaction solution was added an aqueous saturated sodiumbicarbonate solution, followed by extraction with ethyl acetate. Afterthe solvent was distilled off, the residue was purified by silica gelchromatography to obtain 0.23 g of a compound (A-1).

NMR (CDCl₃) δ ppm: 7.75 (dd, 1H, J=1.8 Hz, 7.5 Hz), 7.34 (dd, J=1.8 Hz,7.5 Hz, 1H), 7.19 (t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.41 (brs, 2H),4.57-4.61 (m, 1H), 3.65 (s, 3H), 3.23 (s, 3H), 1.24-1.77 (m, 10H),0.84-0.89 (m, 3H)

Fifth Step: Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxyl-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-1)

To a DMF (6 mL) solution of(RS)-4-[2-methyloxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylamine (A-1,330 mg) obtained in the fourth step, ethyl3-(4-bromo-2,6-dichlorophenyl)-2-methylacrylate (4, 338 mg) synthesizedin Reference Example 18 described later, anddichlorobistriphenylphosphinepalladium (42 mg) was added triethylamine(0.56 mL), and the mixture was stirred at 85° C. for 16 hours under thecarbon monooxide atmosphere. The reaction solution was added to water,followed by extraction with ethyl acetate. The organic layer was washedwith water, washed with an aqueous saturated sodium chloride solution,and dried with magnesium sulfate. After the solvent was distilled off,purification by column chromatography (hexane:ethyl acetate=4:1)afforded 540 mg of a solid. This solid was dissolved in THF (3 mL),methanol (3 mL), and a 2 mol/L sodium hydroxide aqueous solution (3 mL)were added, and the mixture was stirred at room temperature. Thereaction solution was made acidic with hydrochloric acid, followed byextraction with ethyl acetate. The organic layer was washed with water,washed with an aqueous saturated sodium chloride solution, and driedover magnesium sulfate. After the solvent was distilled off,recrystallization with ethyl acetate afforded 370 mg of a compound(B-1).

NMR (DMSO-d6) δ ppm: 12.99 (brs, 1H), 8.29 (s, 2H), 7.91 (dd, 1H, J=2.1Hz, 7.2 Hz), 7.72 (s, 1H), 7.41 (d, 1H, J=1.5 Hz), 7.24-7.33 (m, 2H),4.55-4.60 (m, 1H), 3.62 (s, 3H), 3.16 (s, 3H), 1.69 (s, 3H), 1.25-1.69(m, 10H), 0.83-0.87 (m, 3H)

Using the same method as the synthesis method described in ReferenceExample 1, compounds (A-2) to (A-16), and compounds (B-2) to (B-16) weresynthesized.

Reference Example 2 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-pentyloxyethyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-2)(RS)-4-[2-methyloxy-3-(1-pentyloxyethyl)phenyl]thiazol-2-ylamine (A-2)

NMR (CDCl₃) δ ppm: 7.74 (dd, 1H, J=2.1 Hz, 7.8 Hz), 7.41 (dd, 1H, J=2.1Hz, 7.8 Hz), 7.19 (t, 1H, J=7.8 Hz), 7.07 (s, 1H), 5.49 (brs, 2H), 4.85(q, 1H, J=6.3 Hz), 3.65 (s, 3H), 3.28-3.33 (m, 2H), 1.54-1.58 (m, 1H),1.45 (d. 3H, J=6.6 Hz), 1.24-1.30 (m, 4H), 0.85-0.90 (m, 3H)

Compound (B-2)

NMR (DMSO-d6) δ ppm: 8.32 (s, 2H), 7.65 (s, 1H), 7.48-7.60 (m, 2H), 7.43(s, 1H), 7.23-7.27 (m, 1H), 4.87 (q, 1H, J=6.3 Hz), 3.55 (s, 3H), 1.87(s, 1.55-1.62 (m, 2H), 1.48 (d, 3H, J=6.3 Hz), 1.26-1.38 (m, 4H),0.86-0.90 (m, 3H)

Reference Example 3 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-3)(RS)-4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylamine (A-3)

NMR (CDCl₃) δ ppm: 7.75 (dd, 1H, J=1.2 Hz, 7.8 Hz), 7.41 (dd, 1H, J=1.2Hz, 7.8 Hz), 7.20 (t, 1H, J=7.8 Hz), 7.08 (s, 1H), 5.48 (brs, 2H), 4.85(q, 1H, J=6.0 Hz), 3.66 (s, 3H), 3.28-3.33 (m, 2H), 1.52-1.59 (m, 1H),1.45 (d, 3H, J=6.3 Hz), 1.24-1.34 (m, 6H), 0.85-0.89 (m, 3H)

Compound (B-3)

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J=1.8Hz, 7.5 Hz), 7.72 (s, 1H), 7.35-7.40 (m, 2H), 7.26 (t, 1H, J=7.5 Hz),4.82 (q, 1H, J=6.3 Hz), 3.62 (s, 3H), 3.16-3.37 (m, 2H), 1.69 (s, 3H),1.18-1.51 (m, 11H), 0.82-0.87 (m, 3H)

Reference Example 4 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{-4-[2-methyloxy-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-4)

NMR (CDCl₃) δ ppm: 7.75 (dd, 1H, J=1.8 Hz, 7.8 Hz), 7.34 (dd, 1H, J=1.8Hz, 7.8 Hz), 7.19 (t, 1H, J=7.8 Hz), 7.08 (s, 1H), 5.48 (brs, 2H),4.57-4.61 (m, 1H), 3.65 (s, 3H), 3.23 (s, 3H), 1.26-1.77 (m, 8H),0.85-0.90 (m, 3H)

Compound (B-4)

NMR (DMSO-d6) δ ppm: 12.98 (brs, 1H), 8.29 (s, 2H), 7.91 (dd, 1H, J=2.4Hz, 7.5 Hz), 7.72 (s, 1H), 7.40 (s, 1H), 7.24-7.33 (m, 2H), 4.56-4.60(m, 1H), 3.62 (s, 3H), 3.16 (s, 3H), 1.69 (s, 3H), 1.25-1.69 (m, 8H),0.83-0.88 (m, 3H)

Reference Example 5 Synthesis of(RS)-(E)-(2,6-dichloro-4-{-4-[3-(1-ethyloxyhexyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-5)(RS)-4-[3-(1-methyloxyhexyl)-2-methyloxyphenyl]thiazol-2-ylamine (A-5)

NMR (CDCl₃) δ ppm: 7.73 (dd, 1H, J=1.8 Hz, 7.5 Hz), 7.38 (dd, 1H, J=1.8Hz, 7.5 Hz), 7.18 (t, 1H, J=7.5 Hz), 7.07 (s, 1H), 5.48 (brs, 2H),4.66-4.70 (m, 1H), 3.64 (s, 3H), 3.31-3.42 (m, 2H), 1.16-1.78 (m, 11H),0.85-0.90 (m, 3H)

Compound (B-5)

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.89 (dd, 1H, J=1.8Hz, 7.8 Hz), 7.71 (s, 1H), 7.22-7.40 (m, 4H), 4.65-4.69 (m, 1H), 3.58(s, 3H), 3.17 (d, 2H, J=4.5 Hz), 1.69 (s, 3H), 1.03-1.69 (m, 11H),0.84-0.88 (m, 3H)

Reference Example 6 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxypentyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-6)(RS)-4-[3-(1-ethyloxypentyl)-2-methyloxyphenyl]thiazol-2-ylamine (A-6)

NMR (CDCl₃) δ ppm: 7.75 (dd, 1H, J=7.5 Hz, 1.8 Hz), 7.34 (dd, 1H, J=7.5Hz, 1.8 Hz), 7.15 (t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.26 (brs, 2H),4.67-4.70 (m, 1H), 3.64 (s, 3H), 3.27 (q, 2H, J=7.0 Hz), 1.56-1.68 (m,2H), 1.20-1.50 (m, 4H), 1.10 (t, 3H, J=7.0 Hz), 0.85 (t, 3H, J=7.0 Hz)

Compound (B-6)

NMR (DMSO-d6) δ ppm: 12.98 (brs, 1H), 8.28 (s, 2H), 7.92 (d, 1H, J=7.5Hz), 7.71 (s, 1H), 7.41 (s, 1H), 7.33 (d, 1H, J=7.6 Hz), 7.25 (t, 1H,J=7.6 Hz), 4.67 (t, 1H, J=6.5 Hz), 3.60 (s, 3H), 3.26 (q, 2H, J=7.0 Hz),1.68 (s, 3H), 1.56-1.68 (m, 2H), 1.20-1.50 (m, 4H), 1.10 (t, 3H, J=7.0Hz), 0.85 (t, 3H, J=7.0 Hz).

Reference Example 7 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-propyloxypentyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-7)(RS)-4-[2-methyloxy-3-(1-propyloxypentyl)phenyl]thiazol-2-ylamine (A-7)

NMR (CDCl₃) δ ppm: 7.75 (dd, 1H, J=7.5 Hz, 1.8 Hz), 7.34 (dd, 1H, J=7.5Hz, 1.8 Hz), 7.15 (t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.26 (brs, 2H),4.67-4.70 (m, 1H), 3.64 (s, 3H), 3.27 (q, 2H, J=7.0 Hz), 1.56-1.68 (m,2H), 1.50-1.60 (m, 2H), 1.20-1.50 (m, 4H), 0.87 (t, 3H, J=7.0 Hz), 0.85(t, 3H, J=7.0 Hz).

Compound (B-7)

NMR (DMSO-d6) δ ppm: 12.98 (brs, 1H), 8.28 (s, 2H), 7.90 (d, 1H, J=7.5Hz), 7.71 (s, 1H), 7.41 (s, 1H), 7.33 (d, 1H, J=7.6 Hz), 7.25 (t, 1H,J=7.6 Hz), 4.67 (t, 1H, J=6.5 Hz), 3.61 (s, 3H), 3.20 (t, 2H, J=7.0 Hz),1.68 (s, 3H), 1.56-1.68 (m, 2H), 1.50-1.60 (m, 2H), 1.20-1.50 (m, 4H),0.90 (t, 3H, J=7.0 Hz), 0.85 (t, 3H, J=7.0 Hz).

Reference Example 8 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{-4-[3-(2,2-dimethylpropyl-1-ethyloxy)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-8)(RS)-4-[3-(2,2-dimethylpropyl-1-ethyloxy)-2-methyloxyphenyl]thiazol-2-ylamine(A-8)

NMR (CDCl₃) δ ppm: 7.73 (dd, 1H, J=7.5 Hz, 1.8 Hz), 7.34 (dd, 1H, J=7.5Hz, 1.8 Hz), 7.13 (t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.26 (brs, 2H), 4.37(s, 1H), 3.60 (s, 3H), 3.22-3.38 (m, 2H), 1.08 (t, 3H, J=7.0 Hz), 0.90(s, 9H).

Compound (B-8)

NMR (DMSO-d6) δ ppm: 12.98 (brs, 1H), 8.28 (s, 2H), 7.90 (d, 1H, J=7.5Hz), 7.68 (s, 1H), 7.40 (s, 1H), 7.29 (d, 1H, J=7.6 Hz), 7.25 (t, 1H,J=7.6 Hz), 4.40 (s, 1H), 3.61 (s, 3H), 3.30 (q, 2H, J=7.0 Hz), 1.68 (s,3H), 1.15 (t, 3H, J=7.0 Hz), 0.89 (s, 9H).

Reference Example 9 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{-4-[3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-9)(RS)-4-[3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylamine(A-9)

NMR (CDCl₃) δ ppm: 7.74 (dd, 1H, J=7.5 Hz, 1.8 Hz), 7.32 (dd, 1H, J=7.5Hz, 1.8 Hz), 7.13 (t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.26 (brs, 2H), 4.37(s, 1H), 3.60 (s, 3H), 3.22-3.38 (m, 2H), 1.56-1.66 (m, 2H), 0.93 (t,3H, J=7.0 Hz), 0.90 (s, 9H).

Compound (B-9)

NMR (DMSO-d6) δ ppm: 12.98 (brs, 1H), 8.28 (s, 2H), 7.92 (d, 1H, J=7.5Hz), 7.68 (s, 1H), 7.40 (s, 1H), 7.31 (d, 1H, J=7.6 Hz), 7.27 (t, 1H,J=7.6 Hz), 4.40 (s, 1H), 3.61 (s, 3H), 3.20 (t, 2H, J=7.0 Hz), 1.68 (s,3H), 1.55-165 (m, 2H), 0.90 (t, 3H, J=7.0 Hz), 0.87 (s, 9H).

Reference Example 10 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-propyloxybutyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-10)(RS)-4-[2-methyloxy-3-(1-propyloxybutyl)phenyl]thiazol-2-ylamine (A-10)

NMR (CDCl₃) δ ppm: 7.74 (d, J=7.5 Hz, 1H), 7.36 (d, 1H, J=7.8 Hz), 7.20(t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.15 (brs, 2H), 4.67-4.74 (m, 1H), 3.64(s, 3H), 3.19-3.36 (m, 2H), 1.50-1.80 (m, 6H), 0.86-0.98 (m, 6H)

Compound (B-10)

NMR (DMSO-d6) δ ppm: 13.00 (brs, 2H), 8.29 (s, 2H), 7.90 (d, 1H, J=7.5Hz), 7.72 (s, 1H), 7.24-7.43 (m, 3H), 4.65-4.72 (m, 1H), 3.61 (s, 3H),3.23 (t, 2H, J=6.3 Hz), 1.30-1.80 (m, 9H), 0.84-0.98 (m, 6H)

Reference Example 11 Synthesis of(RS)-(E)-3-(4-{4-[3-(1-butyloxybutyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}-2,6-dichlorophenyl)-2-methylacrylicacid (B-11)(RS)-4-[3-(1-butyloxybutyl-2-methyloxyphenyl]thiazol-2-ylamine (A-11)

NMR (CDCl₃) δ ppm: 7.74 (d, J=7.5 Hz, 1H), 7.36 (d, 1H, J=7.8 Hz), 7.20(t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.15 (brs, 2H), 4.67-4.74 (m, 1H), 3.64(s, 3H), 3.19-3.36 (m, 2H), 1.50-1.80 (m, 8H), 0.86-0.98 (m, 6H)

Compound (B-11)

NMR (DMSO-d6) δ ppm: 13.01 (brs, 2H), 8.29 (s, 2H), 7.90 (d, 1H, J=7.5Hz), 7.72 (s, 1H), 7.23-7.44 (m, 3H), 4.65-4.72 (m, 1H), 3.61 (s, 3H),3.27 (t, 2H, J=6.3 Hz), 1.30-1.78 (m, 11H), 0.83-0.98 (m, 6H)

Reference Example 12 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxy-3-methylbutyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-12)(RS)-4-[3-(1-ethyloxy-3-methyloxybutyl)-2-methyloxyphenyl]thiazol-2-ylamine(A-12)

NMR (CDCl₃) δ ppm: 7.74 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.8 Hz), 7.20(t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.15 (brs, 2H), 4.76-4.84 (m, 1H), 3.64(s, 3H), 3.30-3.42 (m, 2H), 1.50-1.80 (m, 6H), 0.92-1.02 (m, 6H)

Compound (B-13)

NMR (DMSO-d6) δ ppm: 13.00 (brs, 2H), 8.29 (s, 2H), 7.90 (d, 1H, J=7.5Hz), 7.72 (s, 1H), 7.23-7.44 (m, 3H), 4.65-4.72 (m, 1H), 3.62 (s, 3H),3.27 (t, 2H, J=6.3 Hz), 1.78-1.90 (m, 1H), 1.60-74 (m, 4H), 1.30-1.40(m, 1H), 1.11 (t, 3H, J=6.9 Hz), 0.97 (d, 3H, J=6.3 Hz), 0.93 (d, 3H,J=6.3 Hz)

Reference Example 13 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(2-methyl-1-propyloxypropyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-13)(RS)-4-[2-methyloxy-3-(2-methyl-1-propyloxypropyl)phenyl]thiazol-2-ylamine(A-13)

NMR (CDCl₃) δ ppm: 7.74 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.8 Hz), 7.20(t, 1H, J=7.5 Hz), 7.08 (s, 1H), 5.20 (brs, 2H), 4.36 (d, 1H, J=6.9 Hz),3.60 (s, 3H), 3.15-3.34 (m, 2H), 1.90-2.02 (m, 1H), 1.50-1.63 (m, 2H),1.02 (d, 3H, J=6.6 Hz), 0.91 (t, 3H, J=7.5 Hz), 0.83 (d, 3H, J=6.6 Hz)

Compound (B-13)

NMR (DMSO-d6) δ ppm: 13.00 (brs, 2H), 8.29 (s, 2H), 7.88 (d, 1H, J=7.5Hz), 7.70 (s, 1H), 7.20-7.42 (m, 3H), 4.38 (dz, 1H, J=5.1 Hz), 3.60 (s,3H), 3.20-3.27 (m, 2H), 1.85-1.95 (m, 1H), 1.69 (s, 3H), 1.44-0.55 (m,2H), 0.96 (d, 3H, J=4.8 Hz), 0.88 (t, 3H, J=5.7 Hz), 0.81 (d, 3H, J=5.1Hz)

Reference Example 14 Synthesis of(RS)-(E)-3-(4-{4-[3-(1-butyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}-2,6-dichlorophenyl)-2-methylacrylicacid (B-14)(RS)-4-[3-(1-butyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylamine (A-14)

NMR (CDCl₃) δ ppm: 7.73 (dd, 1H, J=1.8 Hz, 7.8 Hz), 7.36 (dd, 1H, J=1.8Hz, 7.8 Hz), 7.17 (t, 1H, J=7.8 Hz), 7.07 (s, 1H), 5.39 (brs, 2H),4.58-4.62 (m, 1H), 3.64 (s, 3H), 3.24-3.37 (m, 2H), 1.30-1.86 (m, 6H),0.98 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.5 Hz)

Compound (B-14)

NMR (DMSO-d6) δ ppm: 13.00 (brs, 1H), 8.29 (s, 2H), 7.89-7.92 (m, 1H),7.72 (s, 1H), 7.40 (s, 1H), 7.23-7.34 (m, 2H), 4.57-4.61 (m, 1H), 3.61(s, 3H), 3.26-3.30 (m, 3H), 1.69 (s, 3H), 1.26-1.78 (m, 6H), 0.92 (t,3H, J=7.2 Hz), 0.86 (t, 3H, J=7.2 Hz)

Reference Example 15 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-pentyloxypropyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-15)(RS)-4-[2-methyloxy-3-(1-pentyloxypropyl)phenyl]thiazol-2-ylamine (A-15)

NMR (CDCl₃) δ ppm: 7.73 (dd, 1H, J=1.8 Hz, 7.8 Hz), 7.36 (dd, 1H, J=1.8Hz, 7.8 Hz), 7.17 (t, 1H, J=7.8 Hz), 7.07 (s, 1H), 5.33 (brs, 2H),4.58-4.62 (m, 1H), 3.64 (s, 3H), 3.23-3.37 (m, 2H), 1.22-1.86 (m, 8H),0.98 (t, 3H, J=7.2), 0.85-0.90 (m, 3H)

Compound (B-15)

NMR (DMSO-d6) δ ppm: 13.00 (brs, 1H), 8.29 (s, 2H), 7.89-7.92 (m, 1H),7.72 (s, 1H), 7.40 (s, 1H), 7.23-7.34 (m, 2H), 4.56-4.61 (m, 1H), 3.61(s, 3H), 3.25-3.39 (m, 3H), 1.69 (s, 3H), 1.18-1.77 (m, 8H), 0.92 (t,3H, J=7.2 Hz), 0.85 (t, 3H, J=7.2 Hz)

Reference Example 16 Synthesis of(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxy-5-methylhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-16) Compound (B-16)

NMR (DMSO-d6) δ ppm: 12.98 (brs, 2H), 9.29 (s, 1H), 7.89-7.92 (m, 1H),7.72 (s, 1H), 7.41 (s, 1H), 7.24-7.37 (m, 3H), 4.53-4.57 (m, 1H), 3.61(s, 3H), 3.16 (s, 3H), 0.87-1.72 (m, 16H).

Reference Example 17 Synthesis of(E)-3-(4-bromo-2,6-dichlorophenyl)-2-methylacrylic acid ethyl (4)

First Step: Synthesis of 4-bromo-2,6-dichlorobenzaldehyde (6)

4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL),and a 48% hydrogen bromide aqueous solution (120 mL) was added, followedby stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL)was added dropwise thereto, the mixture was stirred for 30 minutes, andmethyl acrylate (200 mL), and water (200 mL) were added, followed bystirring for 1 hour. At room temperature, cuprous oxide (2 g) was added,followed by stirring for 2 hours. The reaction solution was extractedwith ethyl acetate, and purified by column chromatography to obtainmethyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl(E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved indichloromethane, an ozone gas was introduced at −70° C., and ozoneoxidization was performed. To the reaction solution was added dimethylsulfide (40 mL), and this was extracted with ethyl acetate to obtain4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).

NMR (CDCl₃) δ ppm: 10.42 (s, 1H), 7.58 (s, 2H)

Second Step: Synthesis of ethyl(E)-3-(4-bromo-2,6-dichlorophenyl)-2-methylacrylate (4)

Triethylphosphonopropionate (26.3 g) was dissolved in THF (150 mL), aTHF solution of sodium hydride (6.3 g), and4-bromo-2,6-dichlorobenzaldehyde (6, 20 g) obtained in the first stepwas added dropwise, and the mixture was stirred for 2 hours. Thereaction solution was extracted with ethyl acetate, and purified bycolumn chromatography to obtain ethyl(E)-3-(4-bromo-2,6-dichlorophenyl)-2-methylacrylate (6, 21.2 g).

Melting point: 32° C.

NMR (CDCl₃) δ ppm: 7.52 (s, 2H), 7.35 (s, 1H), 4.28 (q, 2H, J=7.0 Hz),1.76 (s, 3H), 1.33 (t, 3H, J=7.0 Hz)

Example 1 Synthesis of(R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (C-1A) and(S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyheptyl)-phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (C-1B)

(RS)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-1) obtained in Reference Example 1 was separated by HPLC columnOJ-RH (registered trademark) manufactured by DAICEL (as an elutingsolvent, a mixed solvent of acetonitrile, water, and trifluoroaceticacid) was to obtain an optically active compound (C-1A) and an opticallyactive compound (C-1B).

Optically Active Compound (C-1A)

Melting point: 162-164° C.

NMR (DMSO-d6) δ ppm: 12.99 (brs, 1H), 8.29 (s, 2H), 7.91 (dd, 1H, J=2.1Hz, 7.2 Hz), 7.72 (s, 1H), 7.41 (d, 1H, J=1.5 Hz), 7.24-7.33 (m, 2H),4.55-4.60 (m, 1H), 3.62 (s, 3H), 3.16 (s, 3H), 1.69 (s, 3H), 1.25-1.69(m, 10H), 0.83-0.87 (m, 3H)

Optical rotation: +25.6 degrees (DMSO, c=1.000, 25° C.)

Optically Active Compound (C-1B)

Melting point: 161-164° C.

NMR (DMSO-d6) δ ppm: 12.99 (brs, 1H), 8.29 (s, 2H), 7.91 (dd, 1H, J=2.1Hz, 7.2 Hz), 7.72 (s, 1H), 7.41 (d, 1H, J=1.5 Hz), 7.24-7.33 (m, 2H),4.55-4.60 (m, 1H), 3.62 (s, 3H), 3.16 (s, 3H), 1.69 (s, 3H), 1.25-1.69(m, 10H), 0.83-0.87 (m, 3H)

Optical rotation: −25.6 degrees (DMSO, c=1.000, 25° C.)

Example 2 Synthesis of(R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (C-3A) and(S)-(−)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (C-3B)

According to the same method as in Example 1, an optically activecompound (C-3A) and an optically active compound (C-3B) were synthesizedfrom(RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid (B-3) obtained in Reference Example 3.

Optically Active Compound (C-3A)

Melting point: 139-141° C.

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J=1.8Hz, 7.5 Hz), 7.72 (s, 1H), 7.35-7.40 (m, 2H), 7.26 (t, 1H, J=7.5 Hz),4.82 (q, 1H, J=6.3 Hz), 3.62 (s, 3H), 3.16-3.37 (m, 2H), 1.69 (s, 3H),1.18-1.51 (m, 11H), 0.82-0.87 (m, 3H)

Optical rotation +4.5 degrees (DMSO, c=1.001, 25° C.)

Optically Active Compound (C-3B)

Melting point: 142-145° C.

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J=1.8Hz, 7.5 Hz), 7.72 (s, 1H), 7.35-7.40 (m, 2H), 7.26 (t, 1H, J=7.5 Hz),4.82 (q, 1H, J=6.3 Hz), 3.62 (s, 3H), 3.16-3.37 (m, 2H), 1.69 (s, 3H),1.18-1.51 (m, 11H), 0.82-0.87 (m, 3H)

Optical rotation −4.5 degrees (DMSO, c=1.001, 25° C.)

Example 3 Synthesis of (C-1B)

First Step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)heptane-1-ol(8)

Under room temperature, a 1M borane THF solution (48 mL) was added to anR-CBS 1M toluene solution (120 mL).1-(3-Bromo-2-methyloxyphenyl)heptane-1-one (7, 13 g) was added, and themixture was stirred for 1 hour. Methanol was added, a solvent wasdistilled off, and the residue was purified by chromatography to obtain(S)-1-(3-bromo-2-methyloxyphenyl)heptane-1-ol (8, 12.86 g, yield 75%).

Optical rotation: −22.7±0.6 degrees (CHCl₃, c=1.008, 21° C.)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.2-1.6 (8H, m), 1.74 (2H,m), 2.09 (1H, brs), 3.88 (3H, s), 4.97 (1H, m), 7.01 (1H, t, J=7.8 Hz),7.37 (1H, dd, J=7.9 Hz, J=1.3 Hz), 7.46 (1H, dd, J=7.9 Hz, J=1.7 Hz)

Second Step: Synthesis of(S)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (9)

(S)-1-(3-bromo-2-methyloxyphenyl)heptanes-1-ol (8, 10 g) obtained in thefirst step was dissolved in DMSO (42.1 mL), a 50% KOH aqueous solution(4.21 mL), and methane iodide (3.1 mL) were added, and the mixture wasstirred for 4 hours. The reaction solution was extracted with isopropylether, and purified by silica gel chromatography to obtain(S)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (9, 8.77 g, 83%).

Optical rotation: −70.2±0.9 degrees (CHCl₃, c=1.050, 21° C.)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.2-1.5 (8H, m), 1.5-1.8 (2H,m), 3.22 (3H, s), 3.85 (3H, s), 4.51 (1H, m), 7.02 (1H, t, J=7.8 Hz),7.33 (1H, dd, J=7.8 Hz, J=1.7 Hz), 7.46 (1H, dd, J=7.9 Hz, J=1.7 Hz)

Third Step: Synthesis of(S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11)

To a THF solution of(S)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (9, 12.5 g)obtained in the second step was added dropwise a 2M isopropyl magnesiumchloride THF solution (44 mL) under ice-cooling. After the reactionsolution was stirred at 45° C. for 3 hours,N-methyloxy-N-methyl-2-chloroacetamide (10, 3.5 g) was added underice-cooling, and the mixture was stirred at room temperature for 1 hour.The reaction solution was extracted with ethyl acetate, and purified bysilica gel chromatography to obtain(S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11).

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.2-1.82 (10H, m), 3.22 (3H,s), 3.78 (3H, s), 4.53 (1H, m), 4.73 (2H, m), 7.24 (1H, t, J=7.6 Hz),7.52 (1H, dd, J=7.6 Hz, J=1.8 Hz), 7.60 (1H, dd, J=7.7 Hz, J=1.8 Hz)

Fourth Step: Synthesis of(S)-4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazole-2-amine (12)

(S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11)obtained in the third step was dissolved in ethanol (30 mL), thiourea(1.4 g) was added, and the mixture was stirred at 100° C. for 3 hours.Extraction with toluene and purification by silica gel chromatographyafforded (S)-4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazole-2-amine(12, 4.22 g, yield 32%).

Optical rotation: −54.8±0.9 degrees (DMSO, c=1.045, 21° C.)

NMR (DMSO-d₆) δ ppm: 0.84 (3H, t, J=6.5 Hz), 1.2-1.5 (8H, m), 1.5-1.8(2H, m), 3.13 (3H, s), 3.62 (3H, s), 4.54 (1H, m), 6.99 (2H, brs), 7.05(1H, s), 7.16 (1H, t, J=7.6 Hz), 7.22 (1H, dd, J=7.5 Hz, J=2.0 Hz), 7.81(1H, dd, J=7.4 Hz, J=2.0 Hz)

Results of powder X-ray diffraction are shown in FIG. 1 and Table.

TABLE 1 relative 2θ d value intensity intensity 10.332 8.55452 59.8 50.410.843 8.1527 22.5 18.9 11.371 7.77554 11 9.2 12.042 7.34333 21.4 18.112.635 7 7.7 6.5 14.094 6.27838 30.1 25.3 14.439 6.12951 10.7 9 16.0165.52906 7.21 6.1 16.386 5.40521 15.8 13.3 16.888 5.24555 24.3 20.517.665 5.01658 41.2 34.7 18.209 4.86789 34.2 28.8 18.515 4.78822 119 10019.729 4.49608 12 10.1 20.773 4.27259 12.3 10.3 21.249 4.17792 10.3 8.621.697 4.09268 33.2 28 22.049 4.02813 13.2 11.1 22.734 3.90828 34.5 2923.107 3.84595 103 87.1 23.775 3.73934 22.9 19.3 24.125 3.68592 18.215.3 24.78 3.58996 15.1 12.7 25.222 3.52804 12.9 10.9 25.44 3.4983 10.99.2 26.026 3.42082 16.6 14 26.761 3.3285 7.58 6.4 27.268 3.26785 17.9 1527.802 3.20621 8.34 7 28.719 3.10589 10.3 8.6 30.86 2.89516 5.89 532.688 2.73725 6.74 5.7 34.001 2.63449 7.14 6 34.988 2.5624 6.58 5.535.352 2.53689 5.72 4.8 36.223 2.47782 5.94 5 37.466 2.39845 8.53 7.238.218 2.35294 15.8 13.3 39.065 2.30387 5.44 4.6 39.546 2.27693 6.48 5.5Diffraction angle of main peak: 2θ = 10.33, 17.7, 18.2, 18.5, and 23.1degrees

Fifth Step: Synthesis of ethyl(S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate(14)

(E)-3,5-dichloro-4-(2-ethyloxycarbonylphenylpropyl)benzoic acid (13,3.82 g) obtained in the following A step was dissolved in ethyl acetate(40 mL), diphenoxyphosphoric acid chloride (3 g), and triethylamine (4.2mL) were added, and(S)-4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazole-2-amine (12, 4g) obtained in the third step was added, and the mixture was stirred atroom temperature for 6 hours. The reaction solution was extracted withethyl acetate and, after purification of silica gel chromatography,ethyl(S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate(14, 7.0 g, yield 95%) was obtained.

Optical rotation: −24.1±0.6 degrees (CHCl₃, c=1.040, 21° C.)

NMR (CDCl₃) δ ppm: 0.88 (3H, t, J=6.5 Hz), 1.2-1.8 (10H, m), 1.37 (3H,t, J=7.1 Hz), 1.77 (3H, d, J=1.4 Hz), 3.23 (3H, s), 3.59 (3H, s), 4.31(2H, q, J=7.1 Hz), 4.56 (1H, m), 7.15 (1H, t, J=7.6 Hz), 7.35 (1H, dd,J=7.6 Hz, J=1.7 Hz), 7.41 (1H, d, J=1.2 Hz), 7.52 (1H, s), 7.67 (1H, dd,J=7.6 Hz, J=1.7 Hz), 7.88 (2H, s), 10.42 (1H, brs)

Sixth Step: Synthesis of(S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylicacid (C-1B)

Ethyl(S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate(14, 6.76 g) obtained in the fifth step was dissolved in THF (20 mL) andethanol (20 mL), a 4 mol/L sodium hydroxide aqueous solution (13.5 mL)was added, and the mixture was stirred at room temperature for 2 hours.The reaction solution was neutralized with hydrochloric acid, andextracted with ethyl acetate. The extraction residue was recrystallizedwith methanol to obtain(S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylicacid (C-1B, 5.8 g, yield 88%).

Optical rotation: −33.3±0.6 degrees (CHCl₃, c=1.067, 21° C.)

NMR (CDCl₃) δ ppm: 0.86 (3H, t, J=6.7 Hz), 1.22-1.82 (10H, m), 1.86 (3H,d, J=1.2 Hz), 3.27 (3H, s), 3.54 (3H, s), 4.61 (1H, m), 7.25 (1H, t,J=7.8 Hz), 7.41 (1H, s), 7.43 (1H, dd, J=7.9 Hz, J=1.8 Hz), 7.52 (1H,dd, J=7.5 Hz, J=1.7 Hz), 7.41 (1H, d, J=1.4 Hz), 8.32 (2H, s), 13.3 (2H,brs)

Results of powder X-ray deffraction are shown in FIG. 2.

Deffraction angle of main peak 2θ=4.2, 6.4, 12.3, 13.2, 23.6, 23.8, and24.7 degrees

A Step: Synthesis of(E)-3,5-dichloro-4-(2-ethyloxycarbonylphenylpropyl)benzoic acid (13)

Triethylphosphonopropionate (4.5 g) was dissolved in THF (15 mL), sodiumhydride (1.59 g) was added under ice-cooling, and the mixture wasstirred for 30 minutes. To the solution was added a solution obtained bydissolving 3,5-dichloro-4-formyl-benzoic acid (3.9 g) in THF (10 mL),and the mixture was further stirred for 1 hour and 20 minutes. Thereaction solution was extracted with ethyl acetate, and a solvent wasdistilled off until a weight including a weight of the solvent became11.7 g. The precipitated crystal was filtered off, and washed with amixed solvent of ethyl acetate and n-heptane (1:2) to obtain 3(E)-3,5-dichloro-4-(2-ethyloxycarbonylphenylpropyl)benzoic acid (13,3.98 g).

Melting point: 145° C.

NMR (CDCl₃) δ ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (q, 2H, J=7.0 Hz),1.79 (s, 3H), 1.38 (t, 3H, J=7.0 Hz)

Results of powder X-ray deffraction are shown in FIG. 3.

TABLE 2 relative 2θ d value intensity intensity 8.108 10.8953 56.3 44.310.78 8.20055 6.2 4.9 16.257 5.44785 127 100 19.185 4.62239 18.4 14.519.968 4.44294 23.9 18.8 22.076 4.02312 4.88 3.8 24.463 3.63573 12.910.2 24.801 3.58703 30.1 23.7 26.232 3.39442 15.5 122 26.63 3.34461 6.885.4 27.294 3.26469 8.86 7 27.871 3.19848 4.55 3.6 30.918 2.88984 5.05 431.317 2.85387 10.5 8.3 32.152 2.78163 10.3 8.1 32.84 2.72495 15.6 12.334.166 2.62214 3.55 2.8 35.122 2.55297 12.8 10.1 36.042 2.48989 4.74 3.737.931 2.37008 13.1 10.3 38.508 2.33593 5.61 4.4 39.028 2.30595 25 19.7Diffraction angle of main peak: 2θ = 8.1, 16.3, 19.2, 20.0, 24.8, and39.0 degrees

Example 4 Synthesis of (C-3B)

First Step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)ethane-1-ol(17)

Using the same method as that of the first step of Example 3, thecompound (17) was obtained from the compound (16) at a yield 77%.

Optical rotation: −23.5±0.6 degrees (CHCl₃, c=1.050, 21° C.)

NMR (CDCl₃) δ ppm: 1.49 (3H, d, J=6.6 Hz), 2.33 (1H, brs), 3.88 (3H, s),5.19 (1H, q, J=6.4 Hz), 7.01 (1H, t, J=7.9 Hz), 7.40 (1H, dd, J=7.7 Hz,J=1.1 Hz), 7.46 (1H, dd, J=8.0 Hz, J=1.4 Hz)

Second Step: Synthesis of(S)-1-bromo-3-(1-hexyloxyethyl)-2-methyloxybenzene (18)

Using the same method as that of the second step of Example 3, thecompound (18) was obtained from the compound (17) at a yield of 96%.

Optical rotation: −29.8±0.6 degrees (CHCl₃, c=1.055, 21° C.)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.2-1.4 (6H, m), 1.42 (3H, d,J=6.5 Hz), 1.54 (2H, m), 3.29 (2H, m), 3.85 (3H, s), 4.78 (1H, q, J=6.4Hz), 7.02 (1H, t, J=7.9 Hz), 7.39 (1H, dd, J=7.8 Hz, J=1.7 Hz), 7.45(1H, dd, J=7.9 Hz, J=1.7 Hz)

Third Step and Fourth Step: Synthesis of(S)-4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazole-2-amine (20)

Using the same method as that of the fourth step of Example 3, thecompound (19) was obtained from the compound (18), subsequentlyaccording to the same method as that of the fourth step, the compound(20) was obtained.

Compound (19)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.2-1.4 (6H, m), 1.45 (3H, d,J=6.6 Hz), 1.55 (2H, m), 3.29 (2H, m), 3.78 (3H, s), 4.73 (2H, m), 4.80(1H, q, J=6.4 Hz), 7.24 (1H, t, J=7.8 Hz), 7.52 (1H, dd, J=7.7 Hz, J=1.8Hz), 7.65 (1H, dd, J=7.7 Hz, J=1.8 Hz)

Compound (20)

Optical rotation: −4.2±0.4 degrees (DMSO, c=1.025, 21° C.)

NMR (CDCl₃) δ ppm: 0.84 (3H, t, J=7.0 Hz), 1.2-1.3 (6H, m), 1.35 (3H, d,J=6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J=6.4Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J=7.7 Hz), 7.27 (1H, dd,J=7.5 Hz, J=1.8 Hz), 7.81 (1H, dd, J=7.6 Hz, J=1.9 Hz)

Results of powder X-ray deffraction are shown in FIG. 4.

TABLE 3 relative 2θ d value intensity intensity 8.173 10.80873 22 6.310.15 8.70733 7.99 2.3 12.044 7.34226 10.3 2.9 12.526 7.06085 29.7 8.512.96 6.82519 25.5 7.3 13.633 6.48972 30.2 8.6 15.455 5.72849 22.7 6.516.399 5.401 350 100 16.74 5.29166 32.3 9.2 17.319 5.1161 6.26 1.817.734 4.99722 6.53 1.9 18.352 4.83027 14.1 4 19.025 4.66083 12 3.419.875 4.46344 20.1 5.8 21.323 4.1635 9.66 2.8 21.65 4.10143 12.7 3.623.026 3.85932 47.5 13.6 23.32 3.81131 18.6 5.3 24.265 3.66492 56.2 16.124.56 3.62162 24.8 7.1 24.944 3.56676 9.41 2.7 25.234 3.52635 7.91 2.325.556 3.48265 8.01 2.3 26.107 3.41041 16.8 4.8 26.453 3.36656 26.6 7.627.523 3.23813 9.86 2.8 28.638 3.11453 5.91 1.7 29.371 3.03844 5.3 1.530.268 2.95039 5.29 1.5 30.78 2.90248 6.06 1.7 32.347 2.76539 7.26 2.133.111 2.70324 5.69 1.6 33.774 2.65169 15.2 4.4 35.952 2.49588 14 436.615 2.45222 9.01 2.6 36.905 2.43363 11.2 3.2 38.207 2.35362 13.7 3.938.784 2.31991 7.98 2.3 Diffraction angle of main peak: 2θ = 12.5, 13.0,13.6, 16.4, 23.0, and 24.3 degrees

Fifth Step: Synthesis of ethyl(S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate(21)

Using the same method as that of the fifth step of Example 3, thecompound (21) was obtained from the compound (20) at a yield of 94%.

Optical rotation: +4.7±0.4 degrees (CHCl₃, c=1.07, 21° C.)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.2-1.35 (6H, m), 1.38 (3H,t, J=7.1 Hz), 1.44 (3H, d, J=6.4 Hz), 1.57 (2H, m), 1.77 (3H, d, J=1.4Hz), 3.30 (2H, m), 3.59 (3H, s), 4.31 (2H, q, J=7.1 Hz), 4.83 (1H, q,J=6.4 Hz), 7.17 (1H, t, J=7.7 Hz), 7.42 (1H, d, J=1.7 Hz), 7.42 (1H, dd,J=7.7 Hz, J=1.8 Hz), 7.51 (1H, s), 7.67 (1H, dd, J=7.6 Hz, J=1.7 Hz),7.89 (2H, s), 10.30 (1H, brs)

Sixth Step: Synthesis of(S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylicacid (C-3B)

Using the same method as that of the sixth step of Example 3, thecompound (C-3B) was obtained from the compound (21) at a yield of 80%.

Optical rotation: −7.0±0.5 degrees (CHCl₃, c=1.040, 21° C.)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.2-1.4 (6H, m), 1.48 (3H, d,J=6.4 Hz), 1.52-1.64 (2H, m), 1.86 (3H, d, J=1.4 Hz), 3.35 (2H, t, J=6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J=6.3 Hz), 7.25 (1H, t, J=7.7 Hz), 7.41(1H, s), 7.49 (1H, dd, J=7.9 Hz, J=1.6 Hz), 7.51 (1H, dd, J=7.5 Hz,J=1.8 Hz), 7.65 (1H, d, J=1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)

Results of powder X-ray deffraction are shown in FIG. 5.

Diffraction angle of main peak: 2θ=17.8, 21.1, 22.5, 23.3, 24.1, and24.4 degrees

Example 5 Synthesis of (C-9B)

First Step: Synthesis of(S)-1-(3-bromo-2-methyloxyphenyl)-2,2-dimethyl-propyl-1-ol (23)

Using the same method as that of the first step of Example 3, thecompound (23) was obtained from the compound (22) at a yield of 86%.

Optical rotation: −6.1±0.4 degrees (CHCl₃, c=1.070, 21° C.)

NMR (CDCl₃) δ ppm: 0.92 (9H, s), 2.06 (1H, brs), 3.83 (3H, s), 4.78 (1H,s), 6.99 (1H, t, J=7.8 Hz), 7.38 (1H, dd, J=7.8 Hz, J=1.6 Hz), 7.46 (1H,dd, J=7.9 Hz, J=1.7 Hz)

Second Step: Synthesis of(S)-1-bromo-3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxybenzene (24)

Using the same method as that of the second step of Example 3, thecompound (24) was obtained from the compound (23) at a yield of 84%.

: +3.2±0.4 degrees (CHCl₃, c=1.080, 21° C.)

NMR (CDCl₃) δ ppm: 0.89 (9H, s), 0.92 (3H, t, J=7.2 Hz), 1.56 (2H, m),3.19 (2H, 3.83 (3H, s), 4.30 (1H, s), 6.98 (1H, t, J=7.9 Hz), 7.34 (1H,dd, J=7.9 Hz, J=1.6 Hz), 7.45 (1H, dd, J=7.8 Hz, J=1.6 Hz)

Third Step and Forth Step: Synthesis of(S)-4-(3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl)thiazole-2-amine(26)

Using the same method as that of the third step of Example 3, thecompound (25) was obtained from the compound (24), and subsequentlyaccording to the same method as that of the fourth step, the compound(26) was obtained.

Compound (25)

NMR (CDCl₃) δ ppm: 0.90 (9H, s), 0.92 (3H, t, J=7.2 Hz), 1.57 (2H, m),3.19 (2H, m), 3.74 (3H, s), 4.32 (1H, s), 4.71 (2H, m), 7.21 (1H, t,J=7.7 Hz), 7.49 (1H, dd, J=7.7 Hz, J=1.8 Hz), 7.61 (1H, dd, J=7.7 Hz,J=1.7 Hz)

Compound (26)

Optical rotation: −93.6±1.2 degrees (DMSO, c=1.070, 21° C.)

NMR (CDCl₃) δ ppm: 0.87 (9H, s), 0.89 (3H, t, J=7.4 Hz), 1.52 (2H, m),3.19 (2H, m), 3.58 (3H, s), 4.37 (1H, s), 6.99 (2H, brs), 7.02 (1H, s),7.14 (1H, t, J=7.7 Hz), 7.21 (1H, dd, J=7.6 Hz, J=2.1 Hz), 7.80 (1H, dd,J=7.4 Hz, J=2.0 Hz)

Fifth Step: Synthesis of ethyl(S)-(E)-3-(2,6-dichloro-4-(4-(3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate(27)

Using the same method as that of the fifth step of Example 3, thecompound (27) was obtained from the compound (26) at a yield of 94%.

Optical rotation: −79.5±1.2 degrees (CHCl₃, c=1.010, 21° C.)

NMR (CDCl₃) δ ppm: 0.89 (9H, s), 0.92 (3H, t, J=7.2 Hz), 1.37 (3H, t,J=7.1 Hz), 1.56 (2H, m), 1.76 (3H, d, J=1.5 Hz), 3.18 (2H, m), 3.53 (3H,s), 4.31 (2H, q, J=7.1 Hz), 4.32 (1H, s), 7.08 (1H, t, J=7.6 Hz), 7.34(1H, dd, J=7.7 Hz, J=1.8 Hz), 7.40 (1H, d, J=1.4 Hz), 7.51 (1H, s), 7.62(1H, dd, J=7.6 Hz, J=1.8 Hz), 7.84 (2H, s), 10.77 (1H, brs)

Sixth Step: Synthesis of(S)-(E)-3-(2,6-dichloro-4-(4-(3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxy)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylicacid (C-9B)

Using the same method as that of the sixth step of Example 3, thecompound (C-9B) was obtained from the compound (27) at a yield of 87%.

Optical rotation: −61.6±0.9 degrees (CHCl₃, c=1.018, 21° C.)

NMR (CDCl₃) δ ppm: 0.90 (9H, s), 0.90 (3H, t, J=7.4 Hz), 1.53 (2H, m),1.69 (3H, d, J=1.1 Hz), 3.21 (2H, m), 3.57 (3H, s), 4.40 (1H, s), 7.24(1H, t, J=7.6 Hz), 7.29 (1H, dd, J=7.7 Hz, J=2.1 Hz), 7.40 (1H, d, J=1.4Hz), 7.68 (1H, s), 7.89 (1H, dd, J=7.4 Hz, J=2.1 Hz), 8.28 (2H, s),12.98 (2H, brs)

Results of powder X-ray diffraction are shown in FIG. 6.

Diffraction angle of main peak: 2θ=13.6, 16.1, 21.2, 23.4, and 24.5degrees

Using the same methods as those of Examples 1 to 5, the followingoptically active compounds can be synthesized.

TABLE 4 Compound No. Compound name C-2A(R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-pentyloxyethyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-2B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-pentyloxyethyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-4A (R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-4B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-5A (R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxyhexyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylic acid C-5B(S)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxyhexyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylic acid C-6A(R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxypentyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylic acid C-6B(S)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxypentyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylic acid C-7A(R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-propyloxypentyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-7B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-propyloxypentyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-8A (R)-(E)-3-(2,6-dichloro-4-{4-[3-(2,2-dimethylpropyl-1-ethyloxy)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid C-8B(S)-(E)-3-(2,6-dichloro-4-{4-[3-(2,2-dimethylpropyl-1-ethyloxy)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid C-9B(S)-(E)-3-(2,6-dichloro-4-{4-[3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid C-10A(R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-propyloxybutyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-10B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-propyloxybutyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid

TABLE 5 Com- pound No. Compound name C-11A(R)-(E)-3-(4-{4-[3-(1-butyloxybutyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}-2,6-dichlorophenyl)-2-methylacrylic acid C-11B(S)-(E)-3-(4-{4-[3-(1-butyloxybutyl)-2-methyloxyphenyl]-thiazol-2-ylcarbamoyl}-2,6-dichlorophenyl)-2-methylacrylic acid C-12A(R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxy-3-methylbutyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylic acidC-12B (S)-(E)-3-(2,6-dichloro-4-{4-[3-(1-ethyloxy-3-methylbutyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylic acidC-13A (R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(2-methyl-1-propyloxypropyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-13B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(2-methyl-1-propyloxypropyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-14A (R)-(E)-3-(4-{4-[3-(1-butyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}-2,6-dichlorophenyl)-2-methylacrylic acid C-14B (S)-(E)-3-(4-{4-[3-(1-butyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}-2,6-dichlorophenyl)-2-methylacrylic acid C-15A(R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-pentyloxypropyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-15B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-pentyloxypropyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2- methylacrylicacid C-16A (R)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxy-5-methylhexyl)phenyl]thiazol-2-ylcarbamoyl}-phenyl)-2- methylacrylic acidC-16B (S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxy-5-methylhexyl)phenyl]thiazol-2-ylcarbamoyl}-phenyl)-2- methylacrylic acid

TEST EXAMPLES Test Example 1 Isolation and Purification ofThrombopoietin (TPO)

Human and mouse TPOs were purchased from R&D Systems.

Test Example 2 TPO Receptor Responsiveness

TPO receptor responsiveness of the compound represented by the formula(I) was measured using TPO-dependent cell strain BaF/hTPOR made byintroducing a human TPO receptor gene into a BaF-B03 cell according tothe method described in Collins et al., J. Cell. Physiol., 137: 293-298(1988). A nucleotide sequence of a gene encoding thrombopoietin receptoris described in Vigon et al., Proc. Natl. Acad. Sci. 89:5640-5644(1992). TPO does not respond to a BaF-B03 cell which is a parent strain.A BAF/hTPOR cell proliferated in a RPMI medium with 10% WEHI-3 culturesolution added thereto was washed with PBS once, suspended in a RPMImedium with no WHEHI-3 culture solution added thereto, and cells wereseeded on a 96-well microplate at a 5×10⁴/well, and the present compoundor TPO was added thereto. After cultured at 37° C. for 20 hours under 5%CO₂ atmosphere, a WST-1 reagent (manufactured by Takara Shuzo, Co., Ltd)being a cell proliferation determination reagent was added, andabsorption at 450 nm was measured after 4 hours. An ED₅₀ value wasdefined as a concentration of a compound exhibiting half-maximumresponsiveness of human TPO, and an ED₅₀ value of each compound is shownin Table 6.

TABLE 6 Compound N ED₅₀ (nM) C-1A 3.09 C-1B 2.08 C-3A 1.40 C-3B 1.09C-9B 0.09

Test Example 3 In Vivo Drug Efficacy Test Using Knock-in Mouse in whicha Transmembrane Site of a Mouse TPO Receptor Gene is Substituted with aHuman Type

The presence or the absence of drug efficacy can be confirmed bycontinuously orally administering a compound (C-1A), a compound (C-1B),a compound (C-3A), a compound (C-3B), or a compound (C-9B) twice a dayfor 2 weeks, collecting blood three days, one week, two weeks, and threeweeks after initiation of initial administration, and confirming thatthe platelet number is increased as compared with a Vehicleadministration group.

PREPARATION EXAMPLE Preparation Example 1

A granule containing the following components is prepared.

Component Optically active compound 10 mg represented by the formula (I)Lactose 700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg

The compound represented by the formula (I) and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve.These are mixed with a V-type mixing machine. To a mixed powder is addeda HPC-L (low viscosity hydroxypropylcellulose) aqueous solution, this iskneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm)and dried. The resulting dry granule is passed through a vibration sieve(12/60 mesh) to obtain a granule.

Preparation Example 2

A capsule filling powder containing the following components isprepared.

Component Optically active compound 10 mg represented by the formula (I)Lactose 79 mg Corn starch 10 mg Magnesium stearate 1 mg 100 mg

The compound represented by the formula (I) and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 sieve.These and magnesium stearate are mixed with a V-type mixing machine. 100mg of 10 trituration is filled into a No. 5 hard gelatin capsule.

Preparation Example 3

A capsule filing granule containing the following components isprepared.

Component Optically active compound 15 mg represented by the formula (I)Lactose 90 mg Corn starch 42 mg HPC-L 3 mg 150 mg

The compound represented by the formula (I), and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve.These are mixed, a HPC-L solution is added to a mixed powder, and thisis kneaded, granulated and dried. The resulting dry granule is adjustedin a particle size, 150 mg of which is filled into a No. 4 hard gelatincapsule.

Preparation Example 4

A tablet containing the following components is prepared.

Component Optically active compound 10 mg represented by the formula (I)Lactose 90 mg Microcrystalline cellulose 30 mg CMC-Na 15 mg Magnesiumstearate 5 mg 150 mg

The compound represented by the formula (I), lactose, microcrystallinecellulose and CMC-Na (carboxymethylcellulose sodium salt) are passedthrough a 60 mesh sieve, and mixed. Magnesium stearate is mixed into amixed powder to obtain a preparation mixed powder. The present mixedpowder is directly compressed to obtain 150 mg of a tablet.

Preparation Example 5

An intravenous preparation is prepared as follows:

Optically active compound represented by the formula (I)  100 mgSaturated fatty acid glyceride 1000 ml

A solution of the above components is intravenously administered to apatient at a rate of 1 ml per minute.

INDUSTRIAL APPLICABILITY

It has been found out that the optically active 4-phenylthiazolederivative has the excellent thrombopoietin agonist activity, exhibits ahigh oral absorbability and/or a high in vivo activity, and apharmaceutical composition containing the compound as an activeingredient is effective as a therapeutic and/or a preventive of a blooddisease accompanied with an abnormality of the blood platelet numbersuch as thrombocytopenia or the like. In addition, it has been found outthat the crystal has a high stability and/or a high purity, and anintermediate has a high stability, and they are useful in preparation ofa 4-phenylthiazole derivative and/or preparation of a pharmaceuticalcomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

[FIG. 1] A powder X-ray diffraction pattern and a peak value thereof ofthe compound (12) crystal obtained in the fourth step of Example 3. Anordinate axis indicates an intensity and an abscissa axis indicates adiffraction angle (2θ, unit: degree).

[FIG. 2] A powder X-ray diffraction pattern and a peak value thereof ofthe compound (C-1B) crystal obtained in the sixth step of Example 3. Anordinate axis indicates an intensity (unit: cps) and an abscissa axisindicates a diffraction angle (2θ, unit: degree).

[FIG. 3] A powder X-ray diffraction pattern and a peak value thereof ofthe compound (13) crystal obtained in the seventh step of Example 3. Anordinate axis indicates an intensity and an abscissa axis indicates adiffraction angle (2θ, unit: degree).

[FIG. 4] A powder X-ray diffraction pattern and a peak value thereof ofthe compound (20) crystal obtained in the fourth step of Example 4. Anordinate axis indicates an intensity and an abscissa axis indicates adiffraction angle (2θ, unit: degree).

[FIG. 5] A powder X-ray diffraction pattern and a peak value thereof ofthe compound (C-3B) crystal obtained in the sixth step of Example 4. Anordinate axis indicates an intensity (unit: cps) and an abscissa axisindicates a diffraction angle (2θ, unit: degree).

[FIG. 6] A powder X-ray diffraction pattern and a peak value thereof ofthe compound (C-9B) crystal obtained in the sixth step of Example 5. Anordinate axis indicates an intensity (unit: cps) and an abscissa axisindicates a diffraction angle (2θ, unit: degree).

1. A pharmaceutical composition containing, as an active ingredient, anoptically active compound represented by the formula (I);

wherein R¹ is a halogen atom or C1-C3 alkyloxy; R² is C1-C8 alkyl; R³ isC1-C8 alkyl; R⁴ and R⁵ are each independently a fluorine atom or achlorine atom; R⁶ is C1-C3 alkyl or C1-C3 alkyloxy; * indicates that acarbon atom marked with an asterisk is an asymmetric carbon, apharmaceutically acceptable salt thereof, or a solvate thereof.
 2. Thepharmaceutical composition according to claim 1, wherein the compositionis a thrombopoietin receptor agonist.
 3. The pharmaceutical compositionaccording to claim 1, wherein the composition is a platelet productionregulating agent.
 4. A crystal of(S)-(E)-3-(2,6-dichloro-4-{4-[2-methyloxy-3-(1-methyloxyheptyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid having a diffraction angle 2θ of a main peak of powder X-raydiffraction of 4.2, 6.4, 12.3, 13.2, 23.6, 23.8, and 24.7 degrees.
 5. Acrystal of(S)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid having a diffraction angle 2θ of a main peak of powder X-raydiffraction of 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees.
 6. Acrystal of(S)-(E)-3-(2,6-dichloro-4-{4-[3-(2,2-dimethyl-1-propyloxypropyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylicacid having a diffraction angle 2θ of a main peak of powder X-raydiffraction of 13.6, 16.1, 21.2, 23.4, and 24.5 degrees.
 7. Apharmaceutical composition containing, as an active ingredient, thecrystal as defined in any one of claims 4 to
 6. 8. The pharmaceuticalcomposition according to claim 7, which is a thrombopoietin receptoragonist.
 9. The pharmaceutical composition according to claim 7, whichis the platelet production regulating agent.
 10. A crystal of ethyl3-(4-carboxy-2,6-dichlorophenyl)-2-methylacrylate having a diffractionangle 2θ of a main peak of powder X-ray diffraction of 8.1, 16.3, 19.2,20.0, 24.8, and 39.0 degrees.
 11. Use of an optically active compoundrepresented by the formula (I):

wherein R¹ is a halogen atom or C1-C3 alkyloxy; R² is C1-C8 alkyl; R³ isC1-C8 alkyl; R⁴ and R⁵ are each independently a fluorine atom or achlorine atom; R⁶ is C1-C3 alkyl or C1-C3 alkyloxy; * indicates that acarbon atom marked with an asterisk is an asymmetric carbon, apharmaceutically acceptable salt thereof, or a solvate thereof forproducing a medicament for regulating a platelet production.
 12. Amethod of regulating a platelet production of a mammal, comprisingadministering an amount exhibiting a therapeutic effect of an opticallyactive compound represented by the formula (I):

wherein R¹ is a halogen atom or C1-C3 alkyloxy; R² is C1-C8 alkyl; R³ isC1-C8 alkyl; R⁴ and R⁵ are each independently a fluorine atom or achlorine atom; R⁶ is C1-C3alkyl or C1-C3 alkyloxy; * indicates that acarbon atom marked with an asterisk is an asymmetric carbon, apharmaceutically acceptable salt thereof, or a solvate thereof to amammal including a human.
 13. Use of the crystal as defined in any oneof claims 4 to 6 for producing a medicament for regulating a plateletproduction.
 14. A method of regulating a platelet production of amammal, comprising administering an amount exhibiting a therapeuticeffect of the crystal as defined in any one of claims 4 to 6 to a mammalincluding a human.